Orally ingested glucose is known to elicit greater insulin release than an intravenous glucose challenge. This is known as the incretin response and is mediated by the release of insulinogenic gut peptides and, possibly neural factors. Recipients of simultaneous pancreas- kidney (SPK) transplants may exhibit an impaired incretin response due to the lack of innervation to the transplanted pancreas. We have used a previously validated methodology (Eaton et al, 1980; Polonsky et al., 1986) to determine individual C-peptide clearance kinetics to properly assess the incretin response in SPK recipients. Type 1 diabetic SPK recipients (n=5); txpl> 6 mo. prior to testing) were compared with age, sex and weight matched non-diabetic control subjects (n=5). Subjects were tested under three experimental conditions: 1) a bolus injection of recombinant human c-peptide (150 ug) with a constant infusion of somatostatin (500 ug/h) for 3 h; 2) an adapted oral glucose tolerance test in which subjects drank 75 g of glucose and blood was drawn over a 5 h period 3) an isoglycemic glucose tolerance test where glucose (20(%) was infused intravenously at a variable rate to mimic glucose concentration profiles after orally ingested glucose. Based on the kinetic parameters from condition 1, insulin secretion rates were determined from the plasma C-peptide concentrations measured following the oral and intravenous glucose challenge. Fasting plasma glucose levels were not significantly different in the SPK recipients vs. the non-diabetic control subjects. Fasting plasma insulin was significantly greater in the transplant vs. the control group (26.5+11.2uU/ml vs. 9.5+1.6 uU/ml; t=2.6, p<0.03). Plasma insulin levels were significantly greater after oral than i.v. glucose challenge in both populations (p<0.0001), suggesting anormal incretin response in the SPK recipients. However, transplant subjects were found to have a greater rate of basal insulin secretion compared with control subjects (117&48 pmol/ml/min vs 65+32, t=2.51, p<0.05). When stimulated insulin secretion was xpressed relative to basal secretion, only the normal subjects exhibited greater insulin secretion (215%) after oral glucose challlenge compared with an increase of 28% in the transplant recipients. These data demonstrate that SPK transplant recipients exhibit attenuated insulin secretion to an oral glucose stimulus, relative to their basal rate of insulin secretion when compared with control subjects. Despite attenuated secretion, it appears that the transplanted pancreas secrets adequate insulin to maintain plasama glucose levels within the normal range.